The deiodinases initiate or terminate thyroid hormone (TH) action. Studies pioneered in my laboratory unveiled that the activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease TH signaling in a tissue- and temporal-specific fashion. In other words, D2 and D3 determine the intensity of thyroid signaling independently of plasma T3 (the biologically active TH. Our studies revealed that these mechanisms can be modulated by a wide variety of signaling molecules such as the hedgehog family of proteins, bile acids, HIF-1, NF-B, and a number of xenobiotic substances. These studies have indicated that deiodinases play a broad role in the control of metabolism, the understanding of which is the focus of this application. Our publications and preliminary data show that the activation of the D2 pathway accelerates energy expenditure. At the same time, disruption of the D2 pathway (D2KO) reduces cold-induced and also diet- induced brown adipose tissue (BAT) thermogenesis. Furthermore, we have found that the D2KO mouse develops a striking metabolic phenotype, including obesity, marked hepatic steatosis, glucose intolerance and insulin resistance. Mechanistically, we found that adult D2KO BAT has a permanent defect that stems from impaired embryonic BAT development, with decreased expression of genes defining BAT identity (Dio2, PGC- 11, UCP1) (12). This discovery underlies a role of deiodinase-controlled TH signaling in brown adipogenesis, with metabolic repercussions for energy homeostasis in adulthood. On the other end of the spectrum, the D3 pathway terminates TH action, decreasing energy expenditure as we have shown in hypoxic myocardium and brain. Our studies indicate that this novel adaptative mechanism is operant in settings ranging from BAT to brain. This proposal investigates the deiodinase paradigm from the perspective of metabolic control, examining the effects of D2 and D3 on metabolic function in adult animals, but also on their role in the development of BAT. The novel findings that (i) D2 plays an important role in the development of BAT, leading to (ii) a metabolic phenotype in adult animals, and that (iii) D3 is induced in response to hypoxia, form the basis of this proposal. PUBLIC HEALTH RELEVANCE: Achieving tissue-specific control of TH is a high-value objective for investigators in the fight against hyperlipidemia. Seen in this light, understanding the metabolic role of deiodinases must be considered a worthy goal, since this group of enzymes represents the best known physiologic mechanism for achieving local/selective control of TH action. Thus, our proposed investigations into the mechanisms underlying this phenotype could have significant implications for our understanding of type 2 diabetes, obesity, and hyperlipidemia, establishing D2 as a drug target in the treatment of the metabolic syndrome. In particular, the finding of hepatic steatosis in D2KO animals offers a tantalizing hint of a previously unexpected role (whether direct or indirect) for D2 in the regulation of hepatic lipid homeostasis.